APPLICANT'S ABSTRACT: The purpose of this project is to develop a controlled laboratory method for evaluating the effects of chronic cocaine use and withdrawal from cocaine in human cocaine abusing volunteers. The DSM-IV describes cocaine withdrawal as a syndrome characterized by dysphoric mood, changes in appetite, fatigue, and sleep disturbances, and it is believed that these symptoms and neurobiologic disruptions consequent to cocaine use contribute to relapse. Clinical studies assessing these phenomena have been conducted primarily in cocaine abusers undergoing detoxification. These studies have significantly contributed to our understanding of the cocaine withdrawal syndrome; however, there are elements of experimental control lacking in this open-label methodology. By developing a laboratory method for cocaine stabilization, it will be possible to control critical factors related to the emergence of withdrawal symptoms, such as the time since last cocaine use, amount of cocaine use, and recency of other drug use. This project proposes a series of three inpatient studies that will develop such a method, and will apply that method to evaluate the consequences of chronic cocaine and cocaine withdrawal in humans. The first study uses a within-subject ascending dose procedure to evaluate the safety, pharmacodynamic, and pharmacokinetic profiles of repeated oral dosing with cocaine across a range of doses. The oral route of administration was selected for use in this model for both safety and pharmacological reasons. The objective is to identify a dosing procedure that produces sustained plasma drug levels in the range commonly achieved during illicit use. The second experiment will assess the time course, magnitude, and nature of cocaine withdrawal under double-blind, placebo-controlled conditions using a between-groups design. Cocaine withdrawal in volunteers who have been stabilized on oral cocaine and abruptly transferred to placebo will be compared to spontaneous withdrawal in placebo-maintained volunteers. The dependent measures will include changes in mood, sleep, appetite, motor activity, and neuroendocrine function. The third experiment will evaluate the effects of chronic cocaine on brain dopamine systems using positron emission tomography. Dopamine-D receptor binding potential will be measured at different times during controlled withdrawal from cocaine in cocaine abusers, and these data will be compared to data obtained from normal drug-free volunteers. In summary, this project proposes to develop a safe and controlled laboratory method of cocaine stabilization and abrupt cessation to evaluate the effects of chronic cocaine in humans. Data from the present studies may lead to a better understanding of the physiological, behavioral, and neurobiological consequences of chronic cocaine abuse. This method may provide an improved strategy for the development of medications that may be useful in preventing relapse and treating cocaine dependence.